not limited in quantity so you can do experiments that you couldn’t dream of before,” he explains. “We make experiments with 15 billion cells – that was impossible before.” The cells readily withstand transportation either frozen or in culture, and the researchers at the University of Lausanne have already sent them as far afield as Australia and America, as well as within Europe. There are a number of challenges to
overcome before tumours of human dendritic cells can be generated. The process
requires the overexpression of
oncogens — genes that cause cancer, which can transform the human cell. This is problematic as it can change the cell behaviour, something not observed in these new cell lines. However as Professor Acha-Orbea points out, many of the screens you can do in mouse dendritic cells are applicable to humans. One of their current lines of
research is the study of what determines whether an immune response is triggered or not. Dendritic cells have receptors that recognize pathogens, but initiating an immune response requires more than one signal. “It needs several different keys that are turned on before it allows an immune response,” explains Professor Acha-Orbea. “Otherwise immunities would develop all the time.” The group at the University of
Lausanne has now identified four different signals that work in synergy. They have also quantitatively compared the response to just one, two or three of those four signals in terms of gene transcription and translation and the stability of proteins and RNA. “That’s a big collaborative project,” says Professor Acha-Orbea. Another line of investigation is
determining the roles of different genes in dendritic cell biology. “We can change gene expression in these cell lines very easily,” he explains. “For example, you can make them express a gene that is known to inhibit certain aspects of the immune response or inhibit its expression.” By having the a cell that secretes a certain factor and another that does not, direct comparisons become possible allowing researchers
to
“We made a mouse that
spontaneously made tumours of dendritic cells”
difference. One
probe
what changes with a single
genetic particularly
intriguing result from the experiments of the researchers
at the
University of Lausanne so far has been the response of T cells, a type of white blood cell
that mediates immunity. “It’s an exciting story in a way,” says Professor Acha- Orbea. “We showed that when we activate these dendritic cells we actually kill cells in the tumour.” The researchers then checked
for the response in normal
dendritic cells in mice and found that the same is true in normal dendritic cells as well. “They are triggered to stimulate a T cell response and when you trigger them to stimulate a T cell response, they die.” He adds that he doesn’t see much interest in this particular result as a means of fighting cancer. Similar pathways for destroying cancer cells have already been identified. However, whether the T cell death benefits or hinders the immune response could have enormous implications for improving vaccinations. The ability to generate dendritic cells in
such quantities has unleashed a wealth of possibilities for future research. As Professor Acha-Orbea points out, “These are thousands of experiments you can do with these things.” The stage is set for many exciting collaborations and developments in dendritic cell biology.
★
An article about the project will be published in Frontiers in Immunology
www.projectsmagazine.eu.com
Project Information AT A GLANCE
Project Title: Dendritic cells by the billion revolutionise immunology research
Project Objective: We generated a mouse model from which we can easily isolate fully functional tumor dendritic cell lines that can be easily obtained in unlimited quantities in the absence of added growth factors. These lines can be derived from transgenic or knockout mice and are easily genetically manipulated in vitro using lentiviral transduction.
Project Duration and Timing: At least until my retirement!
Project Funding: • Swiss National Science Foundation 3.5 Million SFr.
• Histiocytosis Research Trust 450’000 SFr
• American Association of Histiocytosis 75’000 SFr
Project Partners: • Mathias Mann (Mnich, Germany) • Walter Reith (Geneva, Switzerland) • José Villadangos, Melbourne, Australia and many others
Main Contact:
Hans Acha-Orbea Hans Acha-Orbea studied Biochemistry at the ETH Zurich and did his Ph.D. with Zinkernagel and Hengartner before moving to Stanford, USA (McDeviit). After a postdoctoral stay at the Ludwig Institute of Cancer Research he became Professor at the University of Lausanne, Switzerland. His main research interests are immunology, immunological tolerance, B, T and dendritic cell biology.
Contact: Tel: +41 21 6925723 Email:
hans.acha-orbea@
unil.ch Web:
www.unil.ch/ib/page9425.html
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